The present invention relates generally to methods and apparatus for treating or controlling medical, psychiatric or neurological disorders by application of stimulating electrical signals to a selected nerve or nerve bundle. More particularly, the invention resides in techniques for treating patients who suffer from chronic motility disorders of the gastrointestinal system, by selectively modulating electrical activity of the vagus nerve.
The digestive system functions to allow nutrients and other food substances to be processed in a manner for efficient absorption by the cells of the body. Food is ingested, large particles are broken into smaller particles, enzymes are secreted to decompose food molecules, the products of the digestive action are absorbed, and unused residue is eliminated. In the alimentary canal of the digestive system, food and materials which are by-products of the digestive process are moved along by peristalsis--movement resulting from waves of alternate circular contraction and relaxation of the tubular structure of the canal by which the contents are propelled onward.
In the context of the present invention, motility consists of normal spontaneous distensions and contractions of the stomach, intestines, and other portions of the canal to move food through the gastrointestinal tract during the digestive process, and related activity. The disorders of interest for treatment according to the invention include hypomotility, in which contractions are not occurring naturally or are abnormally slow; and hypermotility, which is characterized by abnormally rapid contractions.
Chronic hypomotility disorders of the stomach involve gastric stasis (stagnation of fluids), or delayed gastric emptying. Hypomotility is commonly associated with chronic medical conditions such as gastric ulcer, gastroesophageal reflux (regurgitation of the contents of the stomach into the esophagus), diabetic gastroparesis (a slight paralysis of the muscular coat of the stomach), postvagotomy (attributable to effects of excising part of the vagus nerve in treating chronic ulcer patients), and postgastrectomy (following excision of part of the stomach). The disorder has been classified as being of unknown cause (idiopathic) in some 50% of the cases (M. Sleisenger et al., Gastrointestinal Disease, 4th ed., HBJ, Inc., Phila., 1989, pp. 675-713).
Current forms of therapy for such hypomotility include treatment of the underlying disorder, dietary support, use of drugs with prokinetic agents such as metoclopramide, and surgery. The long term therapeutic value of metoclopramide in patients with idiopathic gastric stasis or gastric ulcer has not been established (Sleisenger et al., ibid.). Further, a loss of effectiveness of the drug's gastrokinetic properties has been observed in long term use for treating diabetic gastroparesis (R. Schade et al., Dig.Dis.Sci., 1985, Jan., 30(1), pp. 10-15).
Chronic hypermotility disorders of the stomach involve a dumping syndrome characterized by epigastric pain, nausea, vomiting, diarrhea, and weakness which typically occur within thirty minutes after meals. The dumping syndrome is commonly associated with chronic postgastric surgical conditions, such as gastroenterostomy (in which a new opening is established between the stomach and intestine), partial gastrectomy, vagotomy with pyloroplasty or antrectomy, and proximal gastric vagotomy. Therapies currently applied for this disorder similarly include dietary support, use of drugs (anticholinergic agents), and remedial surgery.
In contrast, motility disorders of the intestines are commonly associated with chronic medical conditions such as duodenal ulcer (in the small intestine), irritable colon syndrome or diverticulosis (in the large intestine), and diabetes. Often, the disorder is diagnosed as idiopathic. As in the cases of the stomach motility disorders, drug therapy is the treatment of choice for the intestinal variety - cholinergic agents for small intestine motility, and metoclopramide for large intestine motility.
Metoclopramide is most often prescribed among motility patients because hypomotility is more common than hypermotility. At least one study has indicated that this drug is effective in only 60% of patients with diabetic gastroparesis, and in only 25% of patients with prior gastric surgery (e.g., Drug Evaluations, 6th ed., AMA, Chicago, 1986, p. 953). As noted above, evidence also exists that the effectiveness of metoclopramide dissipates with long term use. This appears to be the case at least where diabetes is the underlying disease (Schade et al., ibid). The long term value of the drug has not been established for treating gastric stasis which is either idiopathic or attributed to gastric ulcer.
Another reported disadvantage of metoclopramide therapy is that 20% of user patients experience side effects of drowsiness, restlessness, or anxiety (see M. Sleisenger et al., id.).
A principal aim of the present invention is to provide a new and improved therapy for treating motility disorders which is not only safe and effective but avoids the undesirable side effects that have characterized known treatments such as drug therapy.
According to the invention, motility disorders of the gastrointestinal (GI) system, and especially chronic hypermotility and hypomotility of the stomach, are treated and controlled using vagus nerve stimulation to selectively and controllably modulate the nerve's electrical activity in a predetermined manner to inhibit or stimulate motility of the affected region, according to need.
The vagus nerve plays a substantial role in innervation of the GI tract (S. Ritter, Neuroanatomy and Physiology of Abdominal Vagal Afferents, CRC Press, Florida, 1992, at pages 23 et seq.). Neuroanatomical studies have demonstrated that structures in the central vagal complex, such as the nucleus ambiguus, act as a synaptic point for special visceral efferents of the vagus nerve that innervate striated muscle of the upper GI tract. Also, structures in the dorsal vagal complex, such as the dorsal motor nucleus (DMN), act as a synaptic point for general visceral efferents of the vagus nerve that make synaptic contact with postganglionic neurons in the myenteric plexus of the bowel wall, with connection to the smooth muscle of the GI tract.
In the rat, motor neurons of the DMN begin innervating the GI tract at the stomach, and continue as far as the descending colon. Afferent information from the GI tract travels to higher brain nuclei through the vagus nerve (Ritter, ibid.). Gastric emptying can be inhibited by cholecystokinin (CCK) (K. Kelly, Am.J.Physiol., 239, 1980, at G71-G76), a hormone released from the intestinal wall in the presence of fats in the upper part of the small intestine. CCK bonds with central receptors that lie in the nucleus of the solitary tract connected to the GI tract by the vagus nerve. The action of CCK decreases gastric motility as the small intestine fills with food. The vagus nerve thus plays an important role in transmitting efferent and afferent signals between the higher brain structures and the GI tract.
Two groups of efferent fibers in the vagus-enteris reflex can either increase or decrease gastric motility, and, in some species, can be differentiated based on threshold of electrical stimulation. The excitatory pathway consists of preganglionic cholinergic neurons, releasing acetylcholine that contracts gastric smooth muscle. The vagal inhibitory fibers consist of a cholinergic preganglionic neuron that synapses onto a non-adrenergic, non-cholinergic myenteric neuron. The vasoactive intestinal peptide may be the transmitter used by these neurons (J. H. Meyer, Physiology of the Gastrointestinal Tract, L. R. Johnson ed., Raven Press, N.Y., 1987, pp. 613-629).
Historical data indicates that electrical stimulation of the central cut end of the vagus nerve inhibited ongoing gastric contractions in dogs, cats, rabbits and monkeys (W. J. Page May, J. Physiol., 1904, 31, pp. 261-271), and also that electrical stimulation of peripheral cut stumps of the vagus nerve results in activation of efferent fibers which can produce both inhibition and excitation of gastric motility (B. A. McSwinney, Physiol. Rev., 1931, 11, pp. 478-514). Chemical stimulation of the dorsal vagal complex and the nucleus ambiguus produced gastric contractility in the rat which was interrupted by cutting the vagus nerve (T. Garrick et al, Am. J. Physiol., 256 (6 pt 1):G1011-5, June 1989; P. J. Hornby et al, Am. J. Physiol., 258 (4 pt 1):G637-47, April 1990). Electrical stimulation of the dorsal motor nucleus of the vagus nerve with 100 microA, 50 Hz and 0.2 ms pulse duration increased gastric contractions without affecting gastric acid secretion (H. S. Feng, Am. J. Physiol., 259 (2 pt 1)G321-6, August 1990).
The vagus nerve can also influence motor activity of the small intestine. Peripheral stimulation of an intact cervical vagus nerve produced large contractions of the jejunum and stomach (T. Neya et al, Brain Res., May 28, 1990, 517 (1-2):64-8). Psychologically stressed dogs experienced hypermotility in the jejunum and the duodenum which was eliminated by vagotomy (M. S. Muelas, Rev. Esp. Enferm. Dig., June 1992, 81(6):383-7).
The vagus nerve also influences motor activity of the colon. Vagal efferent stimulation in monkeys increased contractile frequency at all sites in the colon, but after atropine was injected contractile frequency decreased (M. Dapoigny et al, Am. J. Physiol., 262 (2 pt 1):G231-6, February 1992). Stimulation of the hypothalamus or cerebral hemispheres increases or inhibits colonic motility, depending on the area stimulated (Sleisenger et al., id.). Efferent fibers of the vagus respond to gastric distension as well as intestinal distension (L. A. Blackshaw et al, J. Auton. Nerv. Syst., 18, pp. 19-24, 1987; D. Grundy, J. Physiol., 319, pp. 43-52, 1981).